Histamine N-methyltransferase

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Histamine N-methyltransferase
Identifiers
EC no. 2.1.1.8
CAS no. 9029-80-5
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
Search
PMC articles
PubMed articles
NCBI proteins
histamine N-methyltransferase
2aot.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases HNMT , HMT, HNMT-S1, HNMT-S2, MRT51
External IDs OMIM: 605238; MGI: 2153181; HomoloGene: 5032; GeneCards: HNMT; OMA:HNMT - orthologs
EC number 2.1.1.8
Orthologs
SpeciesHumanMouse
Entrez

3176

140483

Ensembl

ENSG00000150540

ENSMUSG00000026986

UniProt

P50135

Q91VF2

RefSeq (mRNA)

NM_001024074
NM_001024075
NM_006895

NM_080462

RefSeq (protein)

NP_001019245
NP_001019246
NP_008826

NP_536710

Location (UCSC) Chr 2: 137.96 – 138.02 Mb Chr 2: 23.89 – 23.94 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Histamine N-methyltransferase (HNMT) is a protein encoded by the HNMT gene in humans. It belongs to the methyltransferases superfamily of enzymes and plays a role in the inactivation of histamine, a biomolecule that is involved in various physiological processes. Methyltransferases are present in every life form including archaeans, with 230 families of methyltransferases found across species.

Contents

Specifically, HNMT transfers a methyl (-CH3) group from S-adenosyl-L-methionine (SAM-e) to histamine, forming an inactive metabolite called Nτ-methylhistamine, in a chemical reaction called Nτ-methylation. In mammals, HNMT operates alongside diamine oxidase (DAO) as the only two enzymes responsible for histamine metabolism; however, what sets HNMT apart is its unique presence within the central nervous system (CNS), where it governs histaminergic neurotransmission, that is a process where histamine acts as a messenger molecule between the neurons—nerve cells—in the brain. By degrading and regulating levels of histamine specifically within the CNS, HNMT ensures the proper functioning of neural pathways related to arousal, appetite regulation, sleep-wake cycles, and other essential brain functions.

Research on knockout mice—that are genetically modified mice lacking the Hnmt gene—has revealed that the absence of this enzyme leads to increased brain histamine concentrations and behavioral changes such as heightened aggression and disrupted sleep patterns. These findings highlight the critical role played by HNMT in maintaining normal brain function through precise regulation of neuronal signaling involving histamine. Genetic variants affecting HNMT activity have also been implicated in various neurological disorders like Parkinson's disease and attention deficit disorder.

Gene

Histamine N-methyltransferase is encoded by a single gene, called HNMT, which has been mapped to chromosome 2 in humans. [5]

Three transcript variants have been identified for this gene in humans, which produce different protein isoforms [6] [5] due to alternative splicing, which allows a single gene to code for multiple proteins by including or excluding particular exons of a gene in the final mRNA produced from that gene. [7] [8] Of those isoforms, only one has histamine-methylating activity. [6]

In the human genome, six exons from the 50-kb HNMT contribute to forming a unique mRNA species, approximately 1.6 kb in size. This mRNA is then translated into the cytosolic enzyme histamine N-methyltransferase, comprising 292 amino acids, of which 130 amino acids are a conserved sequence. [9] [10] HNMT does not have promoter cis-elements, such as TATA and CAAT boxes. [11] [12]

Protein

HNMT is a cytoplasmic protein, [13] meaning that it operates within the cytoplasm of a cell. [14] The cytoplasm fills the space between the outer cell membrane (also known as the cellular plasma membrane) and the nuclear membrane (which surrounds the cell's nucleus). [14] HNMT helps regulate histamine levels by degrading histamine within the cytoplasm, ensuring proper cellular function. [15]

Proteins consist of amino acid residues and form a three-dimensional structure. The crystallographic structure to depict the three-dimensional structure of human HNMT protein was first described in 2001 as a monomeric protein that has a mass of 33 kilodaltons and consists of two structural domains. [16] [17]

The first domain, called the "MTase domain", contains the active site where methylation occurs. It has a classic fold found in many other methyltransferases and consists of a seven-stranded beta-sheet surrounded by three helices on each side. This domain binds to its cofactor, S-adenosyl-L-methionine (SAM-e), which provides the methyl group for Nτ-methylation reactions. [16] [17]

The second domain, called the "substrate binding domain", interacts with histamine, contributing to its binding to the enzyme molecule. This domain is connected to the MTase domain and forms a separate region. It includes an anti-parallel beta sheet along with additional alpha helices and 310 helices. [16] [17]

Species

Histamine N-methyltransferase belongs to methyltransferases, a superfamily of enzymes present in every life form, [10] including archaeans. [18]

These enzymes catalyze methylation, which is a chemical process that involves the addition of a methyl group to a molecule, which can affect its biological function. [10] [17]

To facilitate methylation, methyltransferases transfer a methyl group (-CH3) from a cosubstrate (donor) to a substrate molecule (acceptor), leading to the formation of a methylated molecule. [10] [17] Most methyltransferases use S-adenosyl-L-methionine (SAM-e) as a donor, converting it into S-adenosyl-L-homocysteine (SAH). [10] [17] In various species, members of the methyltransferase superfamily of enzymes methylate a wide range of molecules, including small molecules, proteins, nucleic acids, and lipids. These enzymes are involved in numerous cellular processes such as signaling, protein repair, chromatin regulation, and gene regulation. More than 230 families of methyltransferases have been described in various species. [10] [19]

This specific protein, histamine N-methyltransferase, is found in vertebrates, including mammals, birds, reptiles, amphibians, and fishes, but not in invertebrates and plants. [9] [20] [21]

The complementary DNA (cDNA) of Hnmt was initially cloned from a rat kidney and has since been cloned from human, mouse, and guinea pig sources. [9] Human HNMT shares 55.37% similarity with that of zebrafish, 86.76% with that of mouse, 90.53% with that of dog, and 99.54% with that of chimpanzee. [20] [22] Moreover, expressed sequence tags from cow, pig, and gorilla, as well as genome survey sequences from pufferfish, also exhibit strong similarity to human HNMT, suggesting that it is a highly conserved protein among vertebrates. [16] To understand the role of histamine N-methyltransferase in brain function, researchers have studied Hnmt-deficient (knockout) mice, that were genetically modified to have the Hnmt gene "knocked out", i.e., deactivated. [23] [24] Scientists discovered that disrupting the gene led to a significant rise in histamine levels in the mouse brain that highlighted the role of the gene in the brain's histamine system and suggested that HNMT genetic variations in humans could be linked to brain disorders.

Tissue and subcellular distribution

On subcellular distribution, histamine N-methyltransferase protein in humans is mainly localized to the nucleoplasm (which is an organelle, i.e., a subunit of a cell) and cytosol (which is the intracellular fluid, i.e., a fluid inside cells). In addition, it is localized to the centrosome (another organelle). [25]

In humans, the protein is present in many tissues and is most abundantly expressed in the brain, thyroid gland, bronchus, duodenum, liver, gallbladder, kidney, and skin. [26]

Function

Biological inactivation of histamine via N-methylation by the histamine N-methyltransferase (HNMT) enzyme using S-adenosyl-L-methionine (SAM-e) as a cosubstrate and a donor of methyl (CH3) functional group (the biochemical transformation is depicted as in KEGG reaction R02155). The methyl group from the cosubstrate (denoted by red oval) is transferred to histamine to N position that forms N-methylhistamine (NMT), which has the methyl group attached (denoted by green oval). The conversion of histamine to NMT is shown by the straight arrow. The SAM-e is thereby transformed to S-adenosyl-L-histidine (SAH), a molecule without the methyl group. The conversion of SAM-e to SAH is shown by the curved arrow. HNMT-methylation-of-histamine.svg
Biological inactivation of histamine via N-methylation by the histamine N-methyltransferase (HNMT) enzyme using S-adenosyl-L-methionine (SAM-e) as a cosubstrate and a donor of methyl (CH3) functional group (the biochemical transformation is depicted as in KEGG reaction R02155). The methyl group from the cosubstrate (denoted by red oval) is transferred to histamine to N position that forms N-methylhistamine (NMT), which has the methyl group attached (denoted by green oval). The conversion of histamine to NMT is shown by the straight arrow. The SAM-e is thereby transformed to S-adenosyl-L-histidine (SAH), a molecule without the methyl group. The conversion of SAM-e to SAH is shown by the curved arrow.

The function of the HNMT enzyme is histamine metabolism by ways of Nτ-methylation using S-adenosyl-L-methionine (SAM-e) as the methyl donor, producing Nτ-methylhistamine, which, unless excreted, can be further processed by monoamine oxidase B (MAOB) or by diamine oxidase (DAO). Methylated histamine metabolites are excreted with urine. [16] [17]

In mammals, there are two main ways to inactivate histamine by metabolism: one is through a process called oxidative deamination, which involves the enzyme diamine oxidase (DAO) produced by the AOC1 gene, and the other is through a process called Nτ-methylation, which involves the enzyme N-methyltransferase. [29] In the context of biochemistry, inactivation by metabolism refers to the process where a substance, such as a hormone, is converted into a form that is no longer active or effective (inactivation), via a process where the substance is chemically altered (metabolism). [30] [31] [32] [33]

HNMT and DAO are two enzymes that play distinct roles in histamine metabolism. DAO is primarily responsible for metabolizing histamine in extracellular (outside cells) fluids, [34] [35] [36] which include interstitial fluid [37] [38] (fluid surrounding cells) and blood plasma. [39] Such histamine can be exogenous (from food or intestinal flora) or endogenous (released from granules of mast cells and basophils, such as during allergic reactions). [35] DAO is predominantly expressed in the cells of the intestinal epithelium and placenta but not in the central nervous system (CNS). [36] [40] In contrast, HNMT is expressed in CNS and involved in the metabolism of intracellular (inside cells) histamine, which is primarily endogenous and persistently present. HNMT operates in the cytosol, which is the fluid inside cells. Histamine is required to be carried into the cytosol through transporters [41] such as plasma membrane monoamine transporter (SLC29A4) or organic cation transporter 3 (SLC22A3). HNMT enzyme is found in cells of diverse tissues: neurons and glia, brain, kidneys, liver, bronchi, large intestine, ovary, prostate, spinal cord, spleen, and trachea, etc. [28] [42] [40] While DAO is primarily found in the intestinal epithelium, HNMT is present in a wider range of tissues throughout the body. This difference in location also requires different transport mechanisms for histamine to reach each enzyme, reflecting the distinct roles of these enzymes in histamine metabolism. Another distinction between HNMT and DAO lies in their substrate specificity. While HNMT has a strong preference for histamine, DAO can metabolize other biogenic amines—substances, produced by a life form (like a bacteria or an animal) that has an amine functional group (−NH2). [15] [43] The examples of biogenic amines besides histamine that DAO can metabolize are putrescine and cadaverine; [44] still, DAO has a preference for histamine. [45] Both DAO and HNMT exhibit comparable affinities toward histamine. [40] [46]

In the brain of mammals, histamine takes part in histaminergic neurotransmission, that is a process where histamine acts as a messenger molecule between the neurons—the nerve cells. [47] Histamine neurotransmitter activity is controlled by HNMT, since DAO is not present in the CNS. [5] Consequently, the deactivation of histamine via HNMT represents the sole mechanism for ending neurotransmission within the mammalian CNS. [28] This highlights the key role of HNMT for the histamine system of the brain and the brain function in general. [28]

Physiological and clinical significance

Role in health

Histamine has important roles in human physiology as both a hormone and a neurotransmitter. As a hormone, it is involved in the inflammatory response and itching. It regulates physiological functions in the gut and acts on the brain, spinal cord, and uterus. [48] [49] As a neurotransmitter, histamine promotes arousal and regulates appetite and the sleep-wake cycle. [50] [51] [47] It also affects vasodilation, fluid production in tissues like the nose and eyes, gastric acid secretion, sexual function, and immune responses. [48] [49]

HNMT is the only enzyme in the human body responsible for metabolizing histamine within the CNS, playing a role in brain function. [23] [41]

HNMT plays a role in maintaining the proper balance of histamine in the human body. HNMT is responsible for the breakdown and metabolism of histamine, converting it into an inactive metabolite, Nτ-methylhistamine, [48] [49] which inhibits HNMT gene expression in a negative feedback loop. [52] By metabolizing histamine, HNMT helps prevent excessive levels of histamine from accumulating in various tissues and organs. This enzymatic activity ensures that histamine remains at appropriate levels to carry out its physiological functions without causing unwanted effects or triggering allergic reactions. In the central nervous system, HNMT plays an essential role in degrading histamine, where it acts as a neurotransmitter, since HNMT is the only enzyme in the body that can metabolize histamine in the CNS, ending its neurotransmitter activity. [48] [49]

HNMT also plays a role in the airway response to harmful particles, [53] which is the body's physiological reaction to immune allergens, bacteria, or viruses in the respiratory system. Histamine is stored in granules in mast cells, basophils, and in the synaptic vesicles of histaminergic neurons of the airways. When exposed to immune allergens or harmful particles, histamine is released from these storage granules and quickly diffuses into the surrounding tissues. However, the released histamine needs to be rapidly deactivated for proper regulation, which is a function of HNMT. [54] [55]

Histamine intolerance

Histamine intolerance is a presumed set of adverse reactions to ingested histamine in food believed to be associated with flawed activity of DAO and HNMT enzymes. [56] This set of reactions include cutaneous reactions (such as itching, flushing and edema), gastrointestinal symptoms (such as abdominal pain and diarrhea), respiratory symptoms (such as runny nose and nasal congestion), and neurological symptoms (such as dizziness and headache). [56] [41] However, this link between DAO and HNMT enzymes and adverse reactions to ingested histamine in food is not shared by mainstream science due to insufficient evidence. [56] The exact underlying mechanisms by which deficiency in these enzymes can cause these adverse reactions are not fully understood but are hypothesized to involve genetic factors. [56] Despite extensive research, there are no definitive, objective measures or indicators that could unambiguously define histamine intolerance as a distinct medical condition. [56]

Activity measurements

The activity of HNMT, unlike that of DAO, cannot be measured by blood (serum) analysis. [13] [57]

Organs that produce DAO continuously release it into the bloodstream. DAO is stored in vesicular structures associated with the plasma membrane in epithelial cells. [40] As a result, serum DAO activity can be measured, but not HNMT. This is because HNMT is primarily found within the cells of internal organs like the brain or liver and is not released to the bloodstream. Measuring intracellular HNMT directly is challenging. Therefore, diagnosis of HNMT activity is typically done indirectly by testing for known genetic variants. [40]

Genetic variants

There is a genetic variant, registered in the Single Nucleotide Polymorphism database (dbSNP) as rs11558538, found in 10% of the population worldwide, [58] which means that the T allele presents at position 314 of HNMT instead of a usual C allele (c.314C>T). This variant causes the protein to be synthesized with threonine (Thr) replaced with isoleucine (Ile) at position 105 (p.Thr105Ile, T105I). This variant is described as loss-of-function allele reducing HNMT activity, and is associated with diseases such as asthma, allergic rhinitis, and atopic eczema (atopic dermatitis). For individuals with this variant, the intake of HNMT inhibitors, which hamper enzyme activity, and histamine liberators, which release histamine from the granules of mast cells and basophils, could potentially influence their histamine levels. [59] Still, this genetic variant is associated with a reduced risk of Parkinson's disease. [60] [61] [17]

Experiments involving Hnmt-knockout mice have shown that a deficiency in HNMT indeed leads to increased brain histamine concentrations, resulting in heightened aggressive behaviors and disrupted sleep-wake cycles in these mice. In humans, genetic variants that affect HNMT activity have been implicated in various brain disorders, such as Parkinson's disease and attention deficit disorder, but it remains unclear whether these alterations in HNMT are a primary cause or secondary effect of these conditions. Additionally, reduced histamine levels in cerebrospinal fluid have been consistently reported in patients with narcolepsy and other conditions characterized by excessive daytime sleepiness. The association between HNMT polymorphisms and gastrointestinal diseases is still uncertain. While mild polymorphisms can lead to diseases such as asthma and inflammatory bowel disease, they may also reduce the risk of brain disorders like Parkinson's disease. On the other hand, severe mutations in HNMT can result in intellectual disability. Despite these findings, the role of HNMT in human health is not fully understood and continues to be an active area of research. [28]

Inhibitors

The following substances are known to be HNMT inhibitors: amodiaquine, chloroquine, dimaprit, etoprine, metoprine, quinacrine, SKF-91488, tacrine, and diphenhydramine. [62] [63] HNMT inhibitors may increase histamine levels in peripheral tissues and aggravate conditions associated with histamine excess, such as allergic rhinitis, urticaria, and peptic ulcer disease. As of 2024, the effect of HNMT inhibitors on brain function is not yet fully understood. Research suggests that using new inhibitors of HNMT to increase the levels of histamine in the brain could potentially contribute to improvements in the treatment of brain disorders. [62] [63]

Methamphetamine overdose

HNMT could be a potential target for the treatment of symptoms of methamphetamine overdose. [64] It is a central nervous system stimulant, which can be abused up to the lethal consequences: numerous deaths related to methamphetamine overdoses have been reported. [65] [66] The reasoning behind this is that such overdose often leads to behavioral abnormalities, and it has been observed that elevated levels of histamine in the brain can attenuate these methamphetamine-induced behaviors. Therefore, by targeting HNMT, it might be possible to increase the levels of histamine in the brain, which could, in turn, help to mitigate the effects of a methamphetamine overdose. This effect could be achieved by using HNMT inhibitors. Studies predict that one such inhibitor can be metoprine, which crosses the blood-brain barrier and can potentially increase brain histamine levels by inhibiting HNMT; still, as of 2024, treatment of methamphetamine overdose by HNMT inhibitors is still an area of research. [64]

Nτ-methylhistamine

Nτ-methylhistamine (NτMH), also known as 1-methylhistamine, is a product of Nτ-methylation of histamine in a reaction catalyzed by the HNMT enzyme. [27] [16] [17]

NτMH is considered a biologically inactive metabolite of histamine. [67] [68] [69] NτMH is excreted in the urine and can be measured to estimate the amounts of active histamine in the body. [70] While NτMH has some biological activity on its own, it is much weaker than histamine. NτMH can bind to histamine receptors but has a lower affinity and efficacy than histamine for these receptors, meaning that it binds less strongly and activates them less effectively. Depending on the receptor subtype and the tissue context, NτMH may act as a partial agonist or an antagonist for some histamine receptors. NτMH may have some modulatory effects on histamine signaling, but it is unlikely to cause significant allergic or inflammatory reactions by itself. NτMH may also serve as a feedback mechanism to regulate histamine levels and prevent excessive histamine release. [71] Still, NMT, being a product in a reaction catalyzed by HNMT, may inhibit expression of HNMT in a negative feedback loop. [52]

Urinary NτMH can be measured in clinical settings when systemic mastocytosis is suspected. Systemic mastocytosis and anaphylaxis are typically associated with at least a two-fold increase in urinary NτMH levels, which are also increased in patients taking monoamine oxidase inhibitors and in patients on histamine-rich diets. [70]

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<span class="mw-page-title-main">Monoamine neurotransmitter</span> Monoamine that acts as a neurotransmitter or neuromodulator

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Histamine intolerance is a presumed set of adverse reactions to ingested histamine in food. The mainstream theory accepts that there may exist adverse reactions to ingested histamine, but does not recognize histamine intolerance as a separate condition that can be diagnosed. There is a common suspicion that ingested histamine in persons with deficiencies in the enzymes that metabolize histamine may be responsible for various non-specific health complaints, which some individuals categorize as histamine intolerance, still, histamine intolerance is not recognized as an explicit medical condition with that name in the International Classification of Diseases (ICD) Edition 11, or any previous edition. The scientific proof that supports the idea that eating food containing histamine can cause health problems is currently limited and not consistent.

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References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000150540 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000026986 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 PD-icon.svg This article incorporates public domain material from "HNMT Histamine N-methyltransferase". Reference Sequence collection . National Center for Biotechnology Information. Retrieved 30 November 2020. In mammals, histamine is metabolized by two major pathways: N(tau)-methylation via histamine N-methyltransferase and oxidative deamination via diamine oxidase. This gene encodes the first enzyme which is found in the cytosol and uses S-adenosyl-L-methionine as the methyl donor. In the mammalian brain, the neurotransmitter activity of histamine is controlled by N(tau)-methylation as diamine oxidase is not found in the central nervous system. A common genetic polymorphism affects the activity levels of this gene product in red blood cells. Multiple alternatively spliced transcript variants that encode different proteins have been found for this gene.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  6. 1 2 "UniProt HNMT isoforms". Archived from the original on 29 November 2023. Retrieved 27 November 2023.
  7. ↑ Marasco LE, Kornblihtt AR (April 2023). "The physiology of alternative splicing". Nature Reviews. Molecular Cell Biology. 24 (4): 242–254. doi:10.1038/s41580-022-00545-z. PMID   36229538. S2CID   252896843.
  8. ↑ Rogalska ME, Vivori C, Valcárcel J (April 2023). "Regulation of pre-mRNA splicing: roles in physiology and disease, and therapeutic prospects". Nature Reviews. Genetics. 24 (4): 251–269. doi:10.1038/s41576-022-00556-8. PMID   36526860. S2CID   254809593.
  9. 1 2 3 Barnes WG, Grinde E, Crawford DR, Herrick-Davis K, Hough LB (January 2004). "Characterization of a new mRNA species from the human histamine N-methyltransferase gene". Genomics. 83 (1): 168–171. doi:10.1016/s0888-7543(03)00236-2. PMID   14667820.
  10. 1 2 3 4 5 6 "InterPro". www.ebi.ac.uk. Archived from the original on 29 November 2023. Retrieved 28 November 2023.
  11. ↑ Wang L, Thomae B, Eckloff B, Wieben E, Weinshilboum R (August 2002). "Human histamine N-methyltransferase pharmacogenetics: gene resequencing, promoter characterization, and functional studies of a common 5'-flanking region single nucleotide polymorphism (SNP)". Biochemical Pharmacology. 64 (4): 699–710. doi:10.1016/S0006-2952(02)01223-6. PMID   12167489.
  12. ↑ Reyes-Palomares A, Montañez R, Sánchez-Jiménez F, Medina MA (February 2012). "A combined model of hepatic polyamine and sulfur amino acid metabolism to analyze S-adenosyl methionine availability". Amino Acids. 42 (2–3): 597–610. doi:10.1007/s00726-011-1035-7. PMID   21814788.
  13. 1 2 Heidari A, Tongsook C, Najafipour R, Musante L, Vasli N, Garshasbi M, et al. (October 2015). "Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability". Human Molecular Genetics. 24 (20): 5697–5710. doi:10.1093/hmg/ddv286. PMC   4581600 . PMID   26206890.
  14. 1 2 Rehfeld A, Nylander M, Karnov K (2017). "The Cytoplasm". Compendium of Histology. pp. 27–47. doi:10.1007/978-3-319-41873-5_3. ISBN   978-3-319-41871-1.
  15. 1 2 Verburg KM, Henry DP (1986). Histamine N-Methyltransferase. Vol. 5. Humana Press. doi:10.1385/0-89603-079-2:147. ISBN   978-1-59259-610-2.
  16. 1 2 3 4 5 6 Horton JR, Sawada K, Nishibori M, Zhang X, Cheng X (September 2001). "Two polymorphic forms of human histamine methyltransferase: structural, thermal, and kinetic comparisons". Structure. 9 (9): 837–849. doi:10.1016/s0969-2126(01)00643-8. PMC   4030376 . PMID   11566133.
  17. 1 2 3 4 5 6 7 8 9 10 Li J, Sun C, Cai W, Li J, Rosen BP, Chen J (2021). "Insights into S-adenosyl-l-methionine (SAM)-dependent methyltransferase related diseases and genetic polymorphisms". Mutation Research/Reviews in Mutation Research. 788: 108396. Bibcode:2021MRRMR.78808396L. doi:10.1016/j.mrrev.2021.108396. PMC   8847900 . PMID   34893161.
  18. ↑ Lee YH, Ren D, Jeon B, Liu HW (September 2023). "S-Adenosylmethionine: more than just a methyl donor". Natural Product Reports. 40 (9): 1521–1549. doi:10.1039/d2np00086e. PMC   10491745 . PMID   36891755.
  19. ↑ Schubert HL, Blumenthal RM, Cheng X (June 2003). "Many paths to methyltransfer: a chronicle of convergence". Trends in Biochemical Sciences. 28 (6): 329–335. doi:10.1016/S0968-0004(03)00090-2. PMC   2758044 . PMID   12826405.
  20. 1 2 "HNMT Gene – GeneCards | HNMT Protein | HNMT Antibody". Archived from the original on 5 December 2023. Retrieved 27 November 2023.
  21. ↑ Goulty M, Botton-Amiot G, Rosato E, Sprecher SG, Feuda R (June 2023). "The monoaminergic system is a bilaterian innovation". Nature Communications. 14 (1): 3284. Bibcode:2023NatCo..14.3284G. doi: 10.1038/s41467-023-39030-2 . PMC   10244343 . PMID   37280201.
  22. ↑ PD-icon.svg This article incorporates public domain material from "HNMT histamine N-methyltransferase [Danio rerio (Zebrafish)] – Gene – NCBI". Reference Sequence collection . National Center for Biotechnology Information.
  23. 1 2 Naganuma F, Nakamura T, Yoshikawa T, Iida T, Miura Y, Kárpáti A, et al. (November 2017). "Histamine N-methyltransferase regulates aggression and the sleep-wake cycle". Scientific Reports. 7 (1): 15899. Bibcode:2017NatSR...715899N. doi:10.1038/s41598-017-16019-8. PMC   5698467 . PMID   29162912.
  24. ↑ Ogasawara M, Yamauchi K, Satoh Y, Yamaji R, Inui K, Jonker JW, et al. (May 2006). "Recent advances in molecular pharmacology of the histamine systems: organic cation transporters as a histamine transporter and histamine metabolism". Journal of Pharmacological Sciences. 101 (1): 24–30. doi: 10.1254/jphs.fmj06001x6 . PMID   16648665.
  25. ↑ "Subcellular – HNMT – the Human Protein Atlas". Archived from the original on 29 November 2023. Retrieved 27 November 2023.
  26. ↑ "Tissue expression of HNMT – Summary – the Human Protein Atlas". Archived from the original on 17 October 2023. Retrieved 27 November 2023.
  27. 1 2 "Reaction for Histamine N-methyltransferase [EC:2.1.1.8]". KEGG: Kyoto Encyclopedia of Genes and Genomes. R02155. Archived from the original on 29 November 2023. Retrieved 29 November 2023.
  28. 1 2 3 4 5 Verhoeven WM, Egger JI, Janssen PK, van Haeringen A (December 2020). "Adult male patient with severe intellectual disability caused by a homozygous mutation in the HNMT gene". BMJ Case Reports. 13 (12): e235972. doi:10.1136/bcr-2020-235972. PMC   7735107 . PMID   33310825.
  29. ↑ Kucher AN, Cherevko NA (2018). "Genes of the Histamine Pathway and Common Diseases". Russian Journal of Genetics. 54 (1): 15–32. doi:10.1134/S1022795418010088.
  30. ↑ Midtvedt T (1987). "Metabolism of Endogenous Substances". Frontiers in Microbiology. pp. 79–88. doi:10.1007/978-94-009-3353-8_7. ISBN   978-94-009-3353-8.
  31. ↑ "Pathways of Biotransformation — Phase I Reactions". Drug Metabolism. 2005. pp. 41–128. doi:10.1007/1-4020-4142-X_2. ISBN   978-1-4020-4142-6.
  32. ↑ Caira MR, Ionescu C (10 July 2006). Drug Metabolism: Current Concepts. Springer. ISBN   978-1-4020-4142-6.
  33. ↑ "Drug Metabolism – Clinical Pharmacology". Archived from the original on 27 November 2022. Retrieved 17 April 2024.
  34. ↑ Dou Y, Zhu F, Kotanko P (July 2012). "Assessment of extracellular fluid volume and fluid status in hemodialysis patients: current status and technical advances". Seminars in Dialysis. 25 (4): 377–387. doi:10.1111/j.1525-139X.2012.01095.x. PMID   22686593. Extracellular fluid is distributed in two major sub-compartments: interstitial fluid and plasma
  35. 1 2 Hakl R, Litzman J (2023). "Histamine intolerance". Vnitrni Lekarstvi. 69 (1): 37–40. doi: 10.36290/vnl.2023.005 . PMID   36931880. S2CID   257604532.
  36. 1 2 Maintz L, Schwarzer V, Bieber T, van der Ven K, Novak N (2008). "Effects of histamine and diamine oxidase activities on pregnancy: a critical review". Human Reproduction Update. 14 (5): 485–495. doi: 10.1093/humupd/dmn014 . PMID   18499706.
  37. ↑ Cox JS (October 1971). "Disodium cromoglycate. Mode of action and its possible relevance to the clinical use of the drug". British Journal of Diseases of the Chest. 65 (4): 189–204. doi:10.1016/0007-0971(71)90028-3. PMID   4400180.
  38. ↑ Yamamoto S, Francis D, Greaves MW (December 1977). "Enzymic histamine catabolism in skin and its possible clinical significance: a review". Clinical and Experimental Dermatology. 2 (4): 389–393. doi:10.1111/j.1365-2230.1977.tb01580.x. PMID   414862.
  39. ↑ Boehm T, Reiter B, Ristl R, Petroczi K, Sperr W, Stimpfl T, et al. (March 2019). "Massive release of the histamine-degrading enzyme diamine oxidase during severe anaphylaxis in mastocytosis patients". Allergy. 74 (3): 583–593. doi:10.1111/all.13663. PMC   6590243 . PMID   30418682.
  40. 1 2 3 4 5 Maintz L, Novak N (May 2007). "Histamine and histamine intolerance". The American Journal of Clinical Nutrition. 85 (5): 1185–1196. doi: 10.1093/ajcn/85.5.1185 . PMID   17490952.
  41. 1 2 3 Yoshikawa T, Yanai K (28 September 2016). "Histamine Clearance Through Polyspecific Transporters in the Brain". Histamine and Histamine Receptors in Health and Disease. Handbook of Experimental Pharmacology. Vol. 241. pp. 173–187. doi:10.1007/164_2016_13. ISBN   978-3-319-58192-7. PMID   27679412.
  42. ↑ Borriello F, Iannone R, Marone G (2017). "Histamine Release from Mast Cells and Basophils". Histamine and Histamine Receptors in Health and Disease. Handbook of Experimental Pharmacology. Vol. 241. Springer. pp. 121–139. doi:10.1007/164_2017_18. ISBN   978-3-319-58192-7. PMID   28332048.
  43. ↑ Schwelberger HG, Feurle J, Houen G (November 2017). "Mapping of the binding sites of human histamine N-methyltransferase (HNMT) monoclonal antibodies". Inflammation Research. 66 (11): 1021–1029. doi:10.1007/s00011-017-1086-7. PMC   5633628 . PMID   28791419.
  44. ↑ Kettner L, Seitl I, Fischer L (October 2022). "Recent advances in the application of microbial diamine oxidases and other histamine-oxidizing enzymes". World Journal of Microbiology & Biotechnology. 38 (12): 232. doi:10.1007/s11274-022-03421-2. PMC   9547800 . PMID   36208352.
  45. ↑ Schnedl WJ, Lackner S, Enko D, Schenk M, Mangge H, Holasek SJ (April 2018). "Non-celiac gluten sensitivity: people without celiac disease avoiding gluten-is it due to histamine intolerance?". Inflammation Research. 67 (4): 279–284. doi:10.1007/s00011-017-1117-4. PMID   29181545.
  46. ↑ Schwelberger HG, Ahrens F, Fogel WS, Sánchez-Jiménez F (2013). "Chapter 3 Histamine Metabolism". In Stark H (ed.). Histamine H4 Receptor: A Novel Drug Target in Immunoregulation and Inflammation. pp. 63–102. doi:10.2478/9788376560564.c3. ISBN   978-83-7656-054-0. Archived from the original on 20 April 2024. Retrieved 20 April 2024.
  47. 1 2 Satpati A, Neylan T, Grinberg LT (2023). "Histaminergic neurotransmission in aging and Alzheimer's disease: A review of therapeutic opportunities and gaps". Alzheimer's & Dementia. 9 (2): e12379. doi:10.1002/trc2.12379. PMC   10130560 . PMID   37123051.
  48. 1 2 3 4 Lieberman P (February 2011). "The basics of histamine biology". Annals of Allergy, Asthma & Immunology. 106 (2 Suppl): S2–S5. doi:10.1016/j.anai.2010.08.005. PMID   21277530.
  49. 1 2 3 4 Mochizuki T (2022). "Histamine as an Alert Signal in the Brain". The Functional Roles of Histamine Receptors. Current Topics in Behavioral Neurosciences. Vol. 59. pp. 413–425. doi:10.1007/7854_2021_249. ISBN   978-3-031-16996-0. PMID   34448132. S2CID   237329317.
  50. ↑ Bernardino L (2021). "Histamine in the Crosstalk Between Innate Immune Cells and Neurons: Relevance for Brain Homeostasis and Disease". The Functional Roles of Histamine Receptors. Current Topics in Behavioral Neurosciences. Vol. 59. pp. 261–288. doi:10.1007/7854_2021_235. ISBN   978-3-031-16996-0. PMID   34432259.
  51. ↑ Haas HL, Sergeeva OA, Selbach O (July 2008). "Histamine in the nervous system". Physiological Reviews. 88 (3): 1183–1241. doi:10.1152/physrev.00043.2007. PMID   18626069.
  52. 1 2 Peters LJ, Kovacic JP (August 2009). "Histamine: metabolism, physiology, and pathophysiology with applications in veterinary medicine". Journal of Veterinary Emergency and Critical Care. 19 (4): 311–328. doi:10.1111/j.1476-4431.2009.00434.x. PMID   25164630.
  53. ↑ "UniProt HNMT". Archived from the original on 29 November 2023. Retrieved 27 November 2023.
  54. ↑ Schwartz JC, Arrang JM, Garbarg M, Pollard H, Ruat M (January 1991). "Histaminergic transmission in the mammalian brain". Physiological Reviews. 71 (1): 1–51. doi:10.1152/physrev.1991.71.1.1. PMID   1846044.
  55. ↑ Sande CJ, Njunge JM, Mwongeli Ngoi J, Mutunga MN, Chege T, Gicheru ET, et al. (May 2019). "Airway response to respiratory syncytial virus has incidental antibacterial effects". Nature Communications. 10 (1): 2218. Bibcode:2019NatCo..10.2218S. doi:10.1038/s41467-019-10222-z. PMC   6525170 . PMID   31101811.
  56. 1 2 3 4 5 Reese I, Ballmer-Weber B, Beyer K, Dölle-Bierke S, Kleine-Tebbe J, Klimek L, et al. (2021). "Guideline on management of suspected adverse reactions to ingested histamine: Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergology and Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA) as well as the Swiss Society for Allergology and Immunology (SGAI) and the Austrian Society for Allergology and Immunology (ÖGAI)". Allergologie Select. 5: 305–314. doi:10.5414/ALX02269E. PMC   8511827 . PMID   34651098. Creative Commons by small.svg  This article incorporates textfrom this source, which is available under the CC BY 4.0 license.
  57. ↑ Scott MC, Guerciolini R, Szumlanski C, Weinshilboum RM (March 1991). "Mouse kidney histamine N-methyltransferase: assay conditions, biochemical properties and strain variation". Agents and Actions. 32 (3–4): 194–202. doi:10.1007/BF01980873. PMID   1907425. S2CID   35519684.
  58. ↑ PD-icon.svg This article incorporates public domain material from "rs11558538 RefSNP Report – dbSNP – NCBI". Reference Sequence collection . National Center for Biotechnology Information.
  59. ↑ García-Martín E, Ayuso P, Martínez C, Blanca M, Agúndez JA (May 2009). "Histamine pharmacogenomics". Pharmacogenomics. 10 (5): 867–883. doi:10.2217/pgs.09.26. PMID   19450133.
  60. ↑ Lu Y, Dong CZ, Bao D, Zhong C, Liu K, Chen L, et al. (November 2022). "The Thr105Ile Variant (rs11558538) of the Histamine N-methyltransferase Gene may be associated with Reduced Risk of Parkinson Disease: A Meta-analysis". Genetic Testing and Molecular Biomarkers. 26 (11): 543–549. doi:10.1089/gtmb.2021.0299. PMID   36378841. S2CID   253551556.
  61. ↑ Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E, Agúndez JA (July 2016). "Thr105Ile (rs11558538) polymorphism in the histamine N-methyltransferase (HNMT) gene and risk for Parkinson disease: A PRISMA-compliant systematic review and meta-analysis". Medicine. 95 (27): e4147. doi:10.1097/MD.0000000000004147. PMC   5058861 . PMID   27399132.
  62. 1 2 Horton JR, Sawada K, Nishibori M, Cheng X (October 2005). "Structural basis for inhibition of histamine N-methyltransferase by diverse drugs". Journal of Molecular Biology. 353 (2): 334–344. doi:10.1016/j.jmb.2005.08.040. PMC   4021489 . PMID   16168438.
  63. 1 2 Pavadai L (2012). "Pharmacophore modeling, virtual screening and docking studies to identify novel HNMT inhibitors". Journal of the Taiwan Institute of Chemical Engineers. 43 (4): 493–503. doi:10.1016/j.jtice.2012.01.004.
  64. 1 2 Kitanaka J, Kitanaka N, Hall FS, Uhl GR, Takemura M (2016). "Brain Histamine N-Methyltransferase As a Possible Target of Treatment for Methamphetamine Overdose". Drug Target Insights. 10: 1–7. doi:10.4137/DTI.S38342. PMC   4777238 . PMID   26966348.
  65. ↑ "Meth Overdose Symptoms, Effects & Treatment | BlueCrest". Bluecrest Recovery Center. 17 June 2019. Archived from the original on 16 January 2021. Retrieved 8 October 2020.
  66. ↑ "Overdose Death Rates". National Institute on Drug Abuse. 29 January 2021. Archived from the original on 25 January 2018. Retrieved 8 October 2020.
  67. ↑ Maslinski S, Schippert B, Kovar KA, Sewing KF (1977). "Methylation of histamine in the gastric mucosa". Digestion. 15 (6): 497–505. doi:10.1159/000198040. PMID   913915.
  68. ↑ Murray S, Taylor GW, Karim QN, Bliss P, Calam J (November 2000). "N alpha-methylhistamine: association with Helicobacter pylori infection in humans and effects on gastric acid secretion". Clinica Chimica Acta; International Journal of Clinical Chemistry. 301 (1–2): 181–192. doi:10.1016/s0009-8981(00)00357-0. PMID   11020472.
  69. ↑ Grassmann S, Apelt J, Ligneau X, Pertz HH, Arrang JM, Ganellin CR, et al. (October 2004). "Search for histamine H(3) receptor ligands with combined inhibitory potency at histamine N-methyltransferase: omega-piperidinoalkanamine derivatives". Archiv der Pharmazie. 337 (10): 533–545. doi:10.1002/ardp.200400897. PMID   15476285. S2CID   19755327.
  70. 1 2 Lewiecki M (2013). "Evaluation of the Patient at Risk for Osteoporosis". Chapter 63 - Evaluation of the Patient at Risk for Osteoporosis. Academic Press. pp. 1481–1504. doi:10.1016/B978-0-12-415853-5.00063-7. ISBN   978-0-12-415853-5.
  71. ↑ Mohammed T (2010). "Biological and Pharmacological Aspects of Histamine Receptors and Their Ligands". Biomedical Aspects of Histamine. Springer. pp. 61–100. doi:10.1007/978-90-481-9349-3_4. ISBN   978-90-481-9348-6.

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